Depression is a state of psyche characterized by a spectrum of negative feelings ranging in scope from minor unhappiness to overwhelming despair. Though generally associated with emotional or psychological symptoms, depression can be accompanied by severe pain or other physical symptoms as well; depression is capable of dramatically influencing the lives of those it affects.
Recent data estimate the overall prevalence of depression at about 11.1% of the American population, or nearly 35 million individuals (CDC 2010), and predictive models suggest that up to 50% of the population will experience at least one episode of depression during their lives (Andrews 2005).
The framework underlying the pathogenesis of depression is complex and variable among individuals; both psychological and biological factors influence a person’s state of mind at any given time. For example, emergent research links depression with several metabolic phenomena, including inflammation, insulin resistance, and oxidative stress. Intriguing preliminary data also suggest that mitochondrial dysfunction plays a previously unappreciated role in depression. Moreover, the role of hormones in depression is considerable, including stress hormones (glucocorticoids) and sex hormones (testosterone, estrogen). Many people affected by depression may be suffering from hormonal imbalances that are significantly contributing to their symptoms (Howland 2010).
The mainstream medical establishment relies heavily upon psychoactive drugs that manipulate brain chemistry as the frontline treatment (ICSI 2011). Unfortunately, the success rate of pharmacologic intervention for depression is a mere 50% or less and these medications are fraught with potential side effects, including a proclivity to increase suicidal ideation with some anti-depressant drugs (Prescrire Int. 2011).
Life Extension, on the other hand, acknowledges and appreciates the complex nature of depression and advocates a comprehensive management strategy that includes proactive lifestyle changes, behavioral therapy, hormone restoration, and targeted nutritional support to complement conventional antidepressant treatment and balance brain chemistry holistically.
Types of Depression and Associated Symptoms
Although depression is a clearly defined disorder with mental and physical symptoms, unlike other disorders, doctors cannot diagnose it using a blood panel or other form of lab test. Instead, they use carefully developed clinical guidelines as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM).
Depression is distinguished into various forms. The most common are major depressive disorder and dysthymic disorder.
Major depressive disorder (major depression): Major depressive disorder can be very disabling, preventing the patient from functioning normally. A combination of symptoms sabotages the patient’s ability to sleep, study, work, eat, and enjoy formerly pleasurable activities. Some people may experience only a single episode, while others experience recurrent episodes.
Dysthymic disorder (dysthymia): Dysthymia, also known as chronic mild depression, lasts longer than two years. Symptoms are not disabling or as severe as those of major depression, however the patient finds it difficult to function normally and does not feel well. A person with dysthymia may also experience periods of major depression.
Psychotic depression: Psychotic depression is a severe depressive illness that includes hallucinations, delusions, or withdrawal from reality.
Postpartum depression (postnatal depression): Postpartum depression, also known as postnatal depression (PND), affects 10% to 15% of all women after giving birth. This is not to be confused with the “baby blues,” which a mother may feel briefly after giving birth. The development of a major depressive episode within a few weeks of giving birth likely indicates PND. Sadly, many of these women go undiagnosed and suffer for long periods without treatment and support.
Seasonal affective disorder (SAD): The incidence of SAD increases along with the distance from the equator. A person who develops a depressive illness during the winter months with symptoms that go away during spring or summer may have SAD. Accumulating evidence points to vitamin D deficiency as a contributing factor in SAD and in other forms of depression (Parker 2011).
Bipolar disorder (manic-depressive illness): A patient with bipolar disorder experiences (oftentimes extreme) highs (mania) and lows (depression) in mood. The frequency at which an individual reverts from mania to depression, and vice-versa, determines where they lie on the bipolar spectrum – a diagnostic tool used to measure the severity of bipolar disorder.
A diagnosis of clinical depression requires that the patient experience at least five of the nine symptoms below, as described by the DSM, for most of the day, nearly every day, for at least two weeks. One of the symptoms must be either a constant feeling of sadness, anxiety, and emptiness, or loss of interest in formerly pleasurable activities.
If any of these symptoms affects your relationships and your ability to function at home or work, consult with a health care practitioner qualified to assess and treat depression.
- Constant or transient feelings of sadness, anxiety, and emptiness
- Feeling restless; may experience irritability
- Feeling hopeless
- Feeling worthless or guilty for no reason; suicidal thoughts may occur
- Loss of interest in activities or hobbies once enjoyed; may lose interest in sex
- Disturbed sleep patterns; may sleep too little or too much
- Low energy; fatigue
- Significant weight loss or gain due to a change in eating habits; either loss of appetite or eating too much
- Difficulty concentrating, remembering details, or making decisions
Causes of Depression
Research spanning the last 20 to 30 years has examined a range of influences that contribute to depression. These include genetics, brain chemistry, early life trauma, negative thinking, one’s personality and temperament, stress, and difficulty relating to others (Liu 2010). Moreover, emerging scientific research suggests that metabolic phenomenon such as inflammation, oxidative stress, and hormonal imbalances can cause or exacerbate depression as well (Maes 2011; Wolkowitz 2011).
Impaired Stress Response
When a person experiences stress—whether it’s physical or emotional, internal or external—the body copes through a complex system of adaptive reactions. This response involves the release of glucocorticoids, or stress hormones, which stimulate adaptive changes throughout the body.
A stress response is designed to help us confront or escape danger by redirecting blood flow to the muscles, dilating the pupils, inhibiting digestion, and releasing stored fatty acids and glucose (blood sugar) to be used by the muscles. This process is known as the fight-or-flight response.
The fight-or-flight response originates in the brain. When the hypothalamus, the brain’s “control tower,” perceives a threat, it sends chemical signals to the brain’s pituitary gland, also known as the master hormone gland. The pituitary gland then sends chemical signals to the adrenal glands, which sit atop the kidneys. The adrenal glands then release the stress hormone cortisol, which triggers many of the physiological responses to danger.
Almost all animals share the fight-or-flight response, as it is paramount for survival. Although we were designed to undergo this response on only an occasional basis, modern humans cope with relentless stress. Such things as financial worries, deadline pressures at work or school, emotional challenges, excessive caloric intake, poor diet, obesity, inactivity, and environmental toxins chronically activate the hypothalamic-pituitary-adrenal axis, keeping us in a perpetual fight-or-flight response. The result is an increased rate of cardiovascular disease, diabetes, and mood disorders such as depression and anxiety.
The relationship between chronic stress, depression, and anxiety is complex, but incredibly powerful. For instance, the chronic elevation of glucocorticoids (primarily cortisol) caused by chronic stress actually changes the physical structure of the brain.
Chronic exposure to glucocorticoids shifts dendrites, the branches of neurons that receive signals from other neurons, into less functional patterns. Research links this phenomenon with alterations in mood, short-term memory, and behavioral flexibility (Joëls 2011). Glucocorticoids blunt the brain’s sensitivity to serotonin, the mood-regulating neurotransmitter most often associated with depression. (van Riel 2003; Karten 1999). Chronic stress also increases one’s susceptibility to neuronal damage and impairs neurogenesis, the process by which new neurons are “born” (Joëls 2011).
Interestingly, emerging research suggests that drugs used to treat anxiety and depression may stabilize mood not only by acting on neurotransmitters, but also by regulating the brain’s receptors for stress hormones. (Anacker 2011) These new findings strongly support the importance of controlling the stress response in order to alleviate mood disorders. Indeed, several genetic and epidemiological studies have linked excessive stress, and the inability to adapt efficiently to stress, with increased rates of anxiety and depression (Ströhle 2003; Binder 2010; Bennett 2008).
Fortunately, a number of relaxation techniques and coping styles can improve depression, further emphasizing the role of stress in depression. These approaches include Mindfulness-Based Stress Reduction (McCown 2010), meditation (Newberg 2010), biofeedback (Katsamanis 2007), progressive muscle relaxation (Dusek 2008) and an integrative health approach that combines relaxation, nutrition, and exercise (Dusek 2009).
Recent studies suggest some of these techniques influence genetic activity regulating depression (Dusek 2008). Brain imaging techniques show meditation significantly affects neurotransmitter levels and the activity of various parts of the brain that facilitate relaxation (Newberg 2010).
Traumatic events and Post-Traumatic Stress Disorder
Research establishes that trauma, such as the sudden loss of a family member, sexual abuse, or war-related traumas, contributes significantly to prolonged periods of depression. The effects are more pronounced when the trauma occurs in childhood; childhood trauma can considerably alter the structure and function of the brain, increasing susceptibility to depression and anxiety later in life (Nemeroff 2003).
Social network and personal relationships
Lack of meaningful social contact with others has been linked to depression, while evidence increasingly shows that close personal relationships and social networks positively affect mood and health (Grav 2011). Loving relationships, social connection and support, work-related passion and recognition, and a good marriage help prevent depression (Kiecolt-Glaser 2010; Coughlin 2010). Interestingly, it also has been shown that while a good marriage benefits both men and women, it seems to be more important for men from an overall health standpoint.
Magnetic resonance imaging (MRI) shows that the areas of the brain that orechestrate thinking, sleep, mood, appetite, and behavior function abnormally in depressed patients compared to non-depressed individuals. In addition, an imaging technique called single-photon emission computed tomography (SPECT) shows changes in brain blood flow and neurotransmitter activity in the depressed person’s brain. (Yang 2008 Joensuu 2007) Although imaging technology can identify neurotransmitter imbalances, it cannot reveal why depression has occurred.
Depression is more common in those with HIV/AIDS (Wolff 2010), heart disease (Liu 2010), stroke (Morris 2011), cancer (Jayadevappa 2011), diabetes (Stuart 2011), Parkinson's disease (Hemmerle 2011), and many other illnesses. Research shows a person with both depression and a serious illness is more likely to experience severe symptoms and find it harder to adapt to the medical condition. Studies also show that treating depression in this population may improve symptoms of the co-occurring illness in some instances.
Additionally, people dependent on alcohol or narcotics are significantly more likely to be depressed (Shibasaki 2011).
Mainstream Medicine Overlooks Factors that Contribute to Depression
The mainstream view on the cause of depression relies largely on the monoamine hypothesis - a theory proposing that deregulation in neurotransmitter signaling is the sole cause of depression. This has been the grounds for the primary utilization of antidepressant drugs in the management of depression for decades. However, this theory fails to take into account various other well-studied causes, and partly explains the poor success rate of antidepressant medications.
Conventional medicine overlooks several important biological factors that influence depression, thereby undermining the likelihood that a holistic strategy will be employed to thoroughly manage a patient’s depression.
If left unchecked, aberrations among these underappreciated factors may work together to create metabolic and neurochemical imbalances that provoke mood changes and initiate depression.
Critical omissions from conventional assessment of depression include:
- Hormonal imbalances
- Nutritional deficiencies
- Oxidative stress and mitochondrial dysfunction
- Insulin resistance and chronic inflammation
Balanced and youthful concentrations of hormones can help control depression, and astute clinicians often find hormonal imbalances in patients with depression. Because a wide range of hormones can influence depression, it is important to discern which hormone(s) may be an underlying factor when considering depression.
For example, thyroid function directly affects metabolism and brain function, and low thyroid activity can contribute to depression. Conventional medicine relies on overly broad thyroid lab ranges, failing to recognize many cases of sub-optimal thyroid function.
Overt hypothyroidism has been shown to perturb serotonin signaling in the brain, which can contribute to depression (Stipcevic 2009). Furthermore, because the brain requires sufficient thyroid hormones to function optimally, a low thyroid hormone status can contribute to overall loss of function and degeneration in the brain, including the areas of the brain that govern mood (Davis 2007). Hashimoto’s thyroiditis, an autoimmune thyroid disease, can cause a person’s metabolism to swing between overly active to overly depressed. These swings can mimic the symptoms of bipolar disorder and cause misdiagnosis and inappropriate treatment (Chang 1998; Kupka 2002; Cole 2002; Frye 1999).
Sex hormones also influence mood and depression. Women are more susceptible to anxiety than men and also experience more depression when they are pregnant, postpartum, premenstrual and menopausal than at other times in life. These general observations have piqued the interest of scientists and given rise to an expanding body of research linking depression with sex hormone imbalances.
By now, it is well known that most steroid hormones (e.g., pregnenolone, estrogen, progesterone, testosterone, and DHEA) are neurologically active. In fact, the brain contains large numbers of receptors for DHEA, estrogen, and progesterone. These hormones affect many functions in the brain, including the regulation of mood.
Accordingly, a number of studies link hormonal imbalances to various depressive disorders (Cunningham 2009; Parcells 2010; Bloch 2011; Sundermann 2010). In the follicular phase of menses, when estrogen levels are high, women produce more serotonin and experience an improved mood. When estrogen decreases during the premenstrual period, serotonin levels drop, contributing to the negative mood and personality shifts associated with PMS (Kikuchi 2010).
Likewise, the drop in estrogen during menopause is associated with reduced serotonin production and a negative impact on mood and cognition. This is evidenced by the fact that SSRIs have been shown to improve mood and cognitive function in menopausal women (Cubeddu 2010).
In addition, testosterone deficiency has been linked with depression in men, which is not surprising since testosterone plays an important role in brain function, including mood regulation (Zitzmann 2006; Delhez 2003). In studies, select populations of men were more likely to be depressed if their total and/or free testosterone levels are low; these included those with heart disease, HIV/AIDS, and the elderly (Jankowska 2010; Zarrouf 2009).
Medical research acknowledges the link between hormonal imbalances and depression; however, conventional doctors rarely evaluate and address hormone status when treating depression. Instead, they frequently dismiss such imbalances as a normal part of aging, while in truth, restoring youthful hormonal status may effectively combat multiple health deficits associated with aging, including mood imbalances.
The role of hormones in treating depression will be examined more closely in the section of this chapter entitled “Hormone Restoration”.
Nutritional deficiency or insufficiency
Nutrition plays an essential role in brain function, and poor nutrition significantly increases one’s risk for depression. Dietary nutrients influence nervous system function in multiple ways. Important dietary nutrients include:
- B-complex vitamins: B-complex vitamins serve as cofactors for the production of neurotransmitters. Inadequate levels of B-vitamins, especially folate, vitamin B12, niacin, and vitamin B6, can disrupt neurotransmitter synthesis. This not only may lead to mood alterations, but also can impact overall brain function, memory, and cognition.
- Optimal balance of omega-3 and omega-6 fatty acids: Fatty acids are critical components of nerve cell membranes and play an important role in neuronal communication. Fatty acid imbalances can impair the transmission of messages between nerve cells, leading to cognitive deficits and mood alterations, including depression (Yehuda 2005).
- Vitamin D activity: A vitamin-D insufficiency, which is very common even among dedicated supplement users (Faloon 2010), is linked with seasonal depression. Recent evidence suggests that it also may contribute to general depression through its considerable influence on genetic activity, its ability to control inflammation, and other mechanisms.
It is important to remember that optimal brain function necessitates all of these nutritional aspects be addressed simultaneously.
Oxidative Stress and Mitochondrial Dysfunction
Brain tissue is particularly susceptible to oxidative damage due to its high concentrations of phospholipids and the exhaustive metabolic rate among neurons. A growing body of research suggests that oxidative stress contributes to depression and other brain-related disorders (Hovatta 2010). This is thought to result from either an increase in damaging reactive oxygen species, a decrease in antioxidant defense mechanisms, or a combination of the two. These mechanisms become especially important with advancing age (Wolkowitz 2011).
Newer research sheds light on the critical role of mitochondria and neurotransmission and mood regulation. Mitochondria are the “powerhouses” in each cell that generate energy. In an intriguing study, researchers measured the content of mitochondrial DNA within white blood cells in aging patients who were depressed, and in an age-matched group who were not depressed. The subjects with depression had significantly fewer mitochondria than non-depressed controls, leading researchers to suggest, “mitochondrial dysfunction could be a mechanism of geriatric depression” (Kim 2011). In a similar study, greater numbers of mitochondria in peripheral cells were associated with improved cognitive function in healthy elderly women (Lee 2010).
Preliminary research suggests that two nutrients, coenzyme Q10 and acetyl-L-carnitine, which support mitochondrial function, may influence depression. A small study of 35 depressed patients in comparison to 22 healthy volunteer controls showed that plasma CoQ10 levels were significantly lower in the depressed patients. Levels were also lower in treatment-resistant patients, as well as those with chronic fatigue (Maes, 2009).
Several studies of geriatric depression have investigated acetyl-L-carnitine (Pettigrew 2000). One study compared treatment with acetyl-L-carnitine to the medication amisulpride, an antipsychotic medication commonly used to treat depression. In 204 patients with chronic depression, both acetyl-L-carnitine and the pharmaceutical drug improved symptoms (Zanardi, 2006). Acetyl-L-carnitine also has been found to relieve depression and improve quality of life in patients with liver disease (Malaguarnera 2011), and to ease depressive symptoms significantly in patients with fibromyalgia (Rossini 2007).
Another nutrient, pyrroloquinoline quinine (PQQ), is an enzyme involved in the generation of new mitochondria and the maintenance of antioxidant defense systems (Chowanadisai 2010; Rucker 2009; Tachaparian 2010). Supplemental PQQ has been shown to increase mitochondrial activity levels and to be neuroprotective in animal models (Bauerly 2011; zhang 2006; Zhang 2009). Since fewer mitochondria have been observed in depressed patients (Kim 2011), PQQ may be supportive in this population.
Recent data suggest a direct link between insulin resistance and depression. In a small clinical study, treatment of depressed patients with the insulin-sensitizing drug pioglitazone alleviated depression while simultaneously improving their cardio-metabolic risk profiles (Kemp 2011). Evidence suggests that another popular glucose control agent, metformin, may influence psychiatric health as well (Ohaeri 2011). Individuals who are overweight, have suboptimal glucose control, or have diabetes with concurrent depression may find that losing weight and gaining control over their glucose levels eases their depressive symptoms.
Scientific literature indicates that for optimal health, fasting glucose levels should fall between 70 and 85 mg/dL, and 2-hour postprandial (2 hours after a meal) glucose levels should not exceed 120 mg/dL.
Several studies support the role of inflammation and immune system deregulation in depression. Studies have found elevated levels of inflammatory cytokines (signaling molecules with which immune cells communicate) in patients suffering from major depression (Tsao et al 2006), late-life depression (Craddock et al, 2006), and in patients who do not respond to SSRIs (O’Brien 2007). These cytokines include the interleukins IL-1beta and IL-6, as well as the cytokines INF-gamma and TNFalpha.
Studies show an association between the systemic inflammation marker C-reactive protein (C-RP) and major depression (Cizza 2009). Moreover, elevated CRP levels are associated with a number of other significant health problems such as cardiovascular disease. Life Extension suggests that women target a CRP blood level of less than 1.0 mg/L and men target a level of less than 0.55 mg/L.
In prospective studies involving patients being treated with recombinant cytokines for immune-related conditions, depression is observed to develop after inflammation initiates several other undesirable metabolic cascades. This has lead some researchers to identify depression as a late-stage consequenceof chronic inflammation (Dantzer 2011).
Research innovations suggest that future antidepressant medications may be anti-inflammatory in nature (Christmas 2011).
Conventional Medical Approaches – Challenges and Benefits
As mentioned earlier, mainstream medicine typically relies on antidepressants as first line treatment for depression (ICSI 2011). However, in many cases, this first line treatment is meant with failure. The result is a diagnosis of “treatment resistant depression”, and, if severe enough, more drastic measures will be undertaken in attempt to alleviate depressive symptoms. Instead of addressing the multiple other potential contributors to depression mentioned in the protocol, conventional physicians opt to appease treatment resistant depression with procedures like electroconvulsive therapy, which happens to cause memory loss.
Sadly, though research has given rise to promising new modalities for relieving depression, such as transcranial magnetic stimulation, mainstream medicine has yet to advance past the archaic model of psychiatric medicine that has been in place for decades.
This section of the protocol will discuss typical conventional treatment options and also introduce some promising new techniques that are quickly gaining the attention of patient-minded clinicians.
Medications Typically Used to Treat Depression
Several classes of medications may be employed to treat depression; depending on the patients symptoms and history medications from the following classes are typically utilized.
Most antidepressant medications work by altering signaling within the brain. They do so by manipulating the level of neurotransmitters in the synaptic junction, the finite space between two neurons in which signaling molecules are released and reabsorbed to facilitate neuronal communication.
While antidepressants may temporarily improve mood, they do so in a way that is somewhat artificial and unlikely to be effective for an extended time. There is disturbing evidence that some antidepressants may cause the brain to adapt to their presence, requiring increasing dosage and leading to withdrawal symptoms upon cessation.
Moreover, an underrecognized condition known as antidepressant discontinuation syndrome may arise in as many as 20% of patients upon abrupt discontinuation of an antidepressant medication. This phenomenon is likely the result of the brain having adapted to the medication, and now being deprived of it, malfunctions for a time until it can readapt to the lack of the drug. Symptoms of antidepressant discontinuation syndrome include flu-like symptoms, insomnia, nausea, hyperactivity, and sensory disturbances, among others (Warner 2006).
- Selective serotonin reuptake inhibitors (SSRIs) are one of the most popular class of antidepressants. Fluoxetine (Prozac®), citalopram (Celexa®), and sertraline (Zoloft®) are all SSRIs. They tend to have the fewest side effects of antidepressant drugs. Primary side effects are decreased sexual desire and delayed orgasm. Other side effects—digestive symptoms, headaches, insomnia and anxiousness—often decrease over time (Wilson 2004).
- Serotonin and norepinephrine reuptake inhibitors (SNRIs) include duloxetine (Cymbalta®), venlafaxine (Effexor®), and desvenlafaxine (Pristiq®). The side effects for these medications are similar to those of SSRIs.
- Atypical antidepressants are norepinephrine and dopamine reuptake inhibitors (NDRIs) such as bupropion (Wellbutrin®), trazadone (Desyrel®), and mirtazapine (Remeron®). They have a different mechanism of action and side-effect profile than other antidepressants. For example, NDRIs generally do not cause sexual dysfunction as a side effect; however, they can increase blood pressure and risk of a seizure. Other minor effects include loss of appetite, headaches, dry mouth, nervousness, anxiety, stomach pain, constipation, insomnia, and more.
- Older antidepressants include the tricyclic antidepressants amitriptyline, amoxapine, desipramine (Norpramin®), doxepin, imipramine (Tofranil®), nortriptyline (Pamelor®), protptyline (Vivactil®), trimiptyline (Surmontil®); and the monoamine oxidase inhibitors (MAOIs) tranylcypromine (Parnate®) and phenelzine (Nardil®). Doctors do not use these medications frequently because they tend to have more frequent and severe side effects. For example, tricyclic antidepressants can cause an abnormal heart rhythm and drowsiness. MAOIs can increase the risk of severe reactions to foods, drinks and other medications, as well as significantly increase blood pressure, which may lead to a heart attack or stroke. Other side effects of both these classes of medication include constipation, headaches, anxiety, and dry mouth.
A long-standing treatment still used in conventional medicine is electroconvulsive therapy, or ECT. It is most often reserved for people with suicidal ideation, psychotic depression, or those who have not responded to other treatments. It is reportedly effective in up to 90 % of patients, which is why it is still available (Schneider 2007), although it is important to question the extent of the benefit and how long the effects last.
ECT is associated with short-term memory loss, and it appears that some aspects of memory may be affected for an extended time (Lisanby 2000). Moreover, ECT may negatively influence other realms of cognition unrelated to memory; in fact, one group of reviewers stated that “…clinicians should take the non-memory cognitive effects of ECT into account, and patients should be informed of their existence before they sign consent for ECT” (Calev 1995).